Association of a polymorphism in the TNFR2 gene with low bone mineral density.

Previous genetic linkage data suggested that a gene on chromosome 1p36.2-36.3 might be linked to low bone mineral density (BMD). Here, we examine the gene for tumor necrosis factor receptor 2 (TNFR2), a candidate gene within that interval, for association with low BMD in a group of 159 unrelated individuals. We assess two polymorphic sites within the gene, a microsatellite repeat within intron 4, and a three-nucleotide variation in the 3' untranslated region (UTR) of the gene. The latter has five alleles of which the rarest allele is associated with low spinal BMD Z score (p = 0.008). Lowest mean spinal BMD Z scores were observed for individuals having genotypes that were heterozygous for the rarest allele. No homozygotes for the rarest allele were observed. Preliminary analysis suggests that there is a difference in the genotype frequency distribution between the group with low BMD and a control group.

First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q.

Osteoporosis is characterized by low bone density, and osteopenia is responsible for 1.5 million fractures in the United States annually. In order to identify regions of the genome which are likely to contain genes predisposing to osteopenia, we genotyped 149 members of seven large pedigrees having recurrence of low bone mineral density (BMD) with 330 DNA markers spread throughout the autosomal genome. Linkage analysis for this quantitative trait was carried out using spine and hip BMD values by the classical lod-score method using a genetic model with parameters estimated from the seven families. In addition, non-parametric analysis was performed using the traditional Haseman-Elston approach in 74 independent sib pairs from the same pedigrees. The maximum lod score obtained by parametric analysis in all families combined was +2.08 (theta = 0.05) for the marker CD3D on chromosome 11q. All other combined lod scores from the parametric analysis were less than +1.90, the threshold for suggestive linkage. Non-parametric analysis suggested linkage of low BMD to chromosomes 1p36 (Zmax = +3.51 for D1S450) and 2p23-24 (Zmax = +2.07 for D2S149). Maximum multi-point lod scores for these regions were +2.29 and +2.25, respectively. A third region with associated lod scores above the threshold of suggestive linkage in both single-point and multi-point non-parametric analysis was on chromosome 4qter (Zmax = +2.95 for D4S1539 and Zmax = +2.48 for D4S1554). Our data suggest the existence of multiple genes involved in controlling spine and hip BMD, and indicate several candidate regions for further screening in this and other independent samples.

Treatment with zoledronic acid ameliorates negative geometric changes in the proximal femur following acute spinal cord injury.

Acute spinal cord injury is associated with rapid bone loss and an increased risk of fracture. In this double-blind, randomized, placebo-controlled trial, 17 patients were followed for 1 year after administration of either 4 or 5 mg of zoledronic acid or placebo. Bone mineral density (BMD) and structural analyses of the proximal femur were performed using the hip structural analysis program at entry, 6 months, and 12 months. The 17 subjects completed 12 months of observation, nine receiving placebo and eight zoledronic acid. The placebo group showed a decrease in BMD, cross-sectional area, and section modulus and an increase in buckling ratio at each proximal femur site at 6 and 12 months. Six months after zoledronic acid, BMD, cross-sectional area, and section modulus increased at the femoral neck and intertrochanteric regions and buckling ratio decreased consistent with improved bone stability. However, at 12 months, the femoral narrow-neck values declined to baseline. In contrast to placebo, the intertrochanteric region and femur shaft were maintained at or near baseline through 12 months in the zoledronic acid-treated group. Urine N-telopeptide excretion was increased at baseline and declined in both the placebo and treatment groups during the 12 months of observation. We conclude that a single administration of zoledronic acid will ameliorate bone loss and maintain parameters of bone strength at the three proximal femur sites for 6 months and at the femur intertrochanteric and shaft sites for 12 months.

Correlation of ultrasound velocity in the tibial cortex, calcaneal ultrasonography, and bone mineral densitometry of the spine and femur.

We compared the attributes of tibial cortex speed of sound (SOS) measurements with the SOS and broadband ultrasound attenuation (BUA) of the calcaneus, and bone mineral densities of the lumbar spine and femoral neck in a patient crossover study. The three instruments used in the crossover study were the LUNAR DPX and AchillesTM, and a newly introduced device for measuring tibial cortical SOS, the SoundScanTM 2000. Ultrasound precision determinations on the two instruments were performed with the same group of 10 volunteers, and the bone densitometry precision was derived from 22 patients who were assessed twice in a single visit, with repositioning between spine and hip scans. There were 220 female patients in the clinical study, 28 of whom had thoracic spine fractures, and all had measurements with the three instruments. Of the three instruments, the best precision, or lowest coefficient of variation and standardized coefficient of variation, was obtained with the SoundScanTM 2000; 0.20% and 1.39%, respectively. The tibial SOS correlated more poorly with the lumbar spine and femoral neck bone mineral densities (BMDs) than the calcaneal parameters in 220 patients. Tibial SOS measurements could not distinguish the group with spinal fracture from an age-matched control group to a P < 0.05 level, whereas the lumbar spine BMD and calcaneal BUA and stiffness showed a significant difference. We conclude that the SoundScanTM 2000 system measures propagation of sound in the tibial cortex with great precision, but its role in clinical practice is moot. Yet to be established by a long-term prospective study is its efficacy in predicting fracture risk and how well it reflects bone change in response to treatment of osteoporosis.

A correlative study of ultrasound calcaneal and dual-energy X-ray absorptiometry bone measurements of the lumbar spine and femur in 1000 women.

The objectives of the study were firstly to determine the accuracy of ultrasound calcaneal measurements in the prediction of bone mineral density determinations with dual-energy X-ray absorptiometry (DXA) of the lumbar spine (LS), femoral neck (FN), and Ward's triangle (FW) in a mixed population of 1000 women, unsorted as to diagnosis, and secondly to determine the accuracy of the various site-specific measurements in predicting each other. Ultrasound measurements [stiffness, speed of sound (SOS) and broadband ultrasound attenuation (BUA)] were made with the Lunar Achilles device, and the bone mineral density (BMD) of the LS, FN and FW were determined with the Lunar DPX. The data were analyzed for correlation, sensitivity, specificity, and accuracy of various paired sites. The coefficients of correlation of the young adult t-scores in the total group between calcaneal stiffness and BMDs of the LS, FN, and FW varied between 0.53 and 0.60. Coefficients for LS versus FN and FW were 0.70 and 0.62, respectively. A comparison of SOS and BUA values obtained at the calcaneus with BMDs of the LS, FN and FW yielded correlation coefficients that varied from 0.54 to 0.56. The general accuracy of prediction of one site by another ranged from 64.2% to 74.4%, where normality was defined as a t-score > -2. It is concluded that no site can predict the status of another site with sufficiently high accuracy to be clinically useful. The role of ultrasound transmission in bone as a predictor of fracture risk is theoretically promising, but has yet to be proved by a long term prospective study.

Calcaneal ultrasonometry: response to treatment in comparison with dual x-ray absorptiometry measurements of the lumbar spine and femur.

The object of this study was to determine the effectiveness of calcaneal ultrasonometry in the prediction of bone mineral changes in the lumbar spine and femoral neck in response to treatment of osteoporosis. There were 673 women in the study who had one or more follow-up measurements between 1 and 4 years after the initial baseline determination for a total of 881 same-day measurements of the calcaneus, spine, and femur. The LUNAR Achilles and LUNAR DPX (LUNAR Corporation, Madison, WI) were used. Patients were divided into three treatment time groups: Group 1, 1-<2 years, n = 461; Group 2, 2-<3 years, n = 278; Group 3, 3-<4 years, n = 142. There were significant increases in the bone mineral density (BMD) of the lumbar spine, femoral neck, and in the broadband ultrasonic attenuation (BUA) of the calcaneus for the three groups. In contrast, a significant decrease in speed of sound (SOS) was obtained in these time frames and the stiffness index remained unchanged. Spearmen correlations showed an inverse relationship between the percent changes in SOS and BUA, the reasons for which are speculative. Correlations between the percent changes in calcaneal parameters and the BMDs of the lumbar spine and femoral neck were weak, whether significant or not, rho varying from -0.12 to 0.20. There was a subset of 371 patient measurements that registered BMD increases in both the lumbar spine and femoral neck. This was considered to be an objective indication of adequate compliance with prescribed treatment. Analysis of this subset yielded parameter correlations similar to those of the entire group. It is concluded that changes in the calcaneal ultrasound parameters in response to treatment of osteoporosis are not a reflection of mineral changes occurring in the lumbar spine and femoral neck in a given individual, and in this regard, calcaneal ultrasonometry is not a substitute for direct-site dual X-ray absorptiometry (DXA) measurement of the lumbar spine and femur.

Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36.

Osteoporosis is a common condition characterized by reduced skeletal strength and increased susceptibility to fracture. Eight million Americans over the age of 50 have osteoporosis of the femoral neck. The most important risk factor for osteoporosis is low bone mineral density (BMD), and several epidemiological studies have shown the importance of genetic factors in determining variability of BMD. An initial genome screen in seven large pedigrees suggested that a candidate region conferring susceptibility to low BMD of the femoral neck was located on chromosome 1p36. We have now confirmed and extended this finding by analyzing nine microsatellite markers spanning a 40 cM interval across the candidate region in an expanded sample of 42 families. Heritability of femoral neck BMD was estimated as 0.51 +/- 0.13 in these families, after accounting for the effects of age, sex, body mass index, height and weight. Variance component linkage analysis yielded a maximum multipoint LOD score of 3.53 for linkage of femoral neck BMD to a quantitative trait locus (QTL) located near marker D1S214. The associated empirical P-value by simulation analysis was equal to 0.0001. The results strongly support the hypothesis that a major QTL controlling femoral neck BMD is located on chromosome 1p36.2-p36.3, and further analysis of candidate genes in this region is warranted.

Osteopenia in 37 members of seven families: analysis based on a model of dominant inheritance.

BACKGROUND: The genetic factors involved in determining bone mineral density (BMD) have not been fully elucidated. We have begun genetic linkage analysis of seven families in which many members are osteopenic, in order to identify chromosomal loci that are potentially involved in determining BMD. MATERIALS AND METHODS: Spine BMD was measured in 143 members of seven kindred with familial osteopenia. The absolute BMD values for the spine (L2-L4) were converted to the age-, gender-, and weight-adjusted Z scores, and this corrected value was used as the quantitative trait on which to base subsequent genetic analyses. Simulations of linkage were performed in order to determine the information content of the pedigree set, and actual linkage analysis was conducted using polymorphic markers either within or near three candidate loci: COL1A1, COL1A2, and vitamin D receptor (VDR). RESULTS: The distribution of the corrected Z scores was bimodal (p = 0.001) suggesting a monogenic mode of inheritance of the low BMD trait. Simulation of linkage analysis suggested that the family data set was sufficient to detect linkage under a single major gene model. Actual linkage analysis did not support linkage to the three candidate loci. In addition, the VDR genotype was not statistically associated with low bone density at the spine. CONCLUSIONS: Loci other than COL1A1, COL1A2 and VDR are very likely responsible for the low BMD trait observed in these families. These families are suitable for a genome-wide screen using microsatellite repeats in order to identify the loci that are involved in osteopenia.

Vitamin D receptor genotype is not associated with bone mineral density in three ethnic/regional groups.

We report a cross-sectional study of 48 men, 56 premenopausal women, and 80 postmenopausal women who were of three ethnic/regional backgrounds: southern European (Greek, Italian), eastern European (Jewish, Polish, Hungarian), and western European (French, British). We determined bone mineral density (BMD) at four skeletal sites and assessed the vitamin D receptor (VDR) genotype by the Bsml restriction site polymorphism. Age and body mass index had significant effects on BMD by multiple regression analysis. In addition, ethnic/regional group had a significant effect on spinal BMD in premenopausal females (P = 0.014) and in males (P = 0.039). However, VDR genotype had no significant effect on BMD in any of the three study groups.